A General and Facile Strategy to Fabricate Multifunctional

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A General and Facile Strategy to Fabricate Multifunctional Nanoprobes for Simultaneous 19F Magnetic Resonance Imaging, Optical/Thermal Imaging and Photothermal Therapy Gaofei Hu, Nannan Li, Juan Tang, Suying Xu, and Leyu Wang ACS Appl. Mater. Interfaces, Just Accepted Manuscript • DOI: 10.1021/acsami.6b05510 • Publication Date (Web): 18 Aug 2016 Downloaded from http://pubs.acs.org on August 19, 2016

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ACS Applied Materials & Interfaces

A General and Facile Strategy to Fabricate Multifunctional Nanoprobes for Simultaneous 19F Magnetic Resonance Imaging, Optical/Thermal Imaging and Photothermal Therapy

Gaofei Hu, Nannan Li, Juan Tang, Suying Xu, and Leyu Wang*

State Key Laboratory of Chemical Resource Engineering, Beijing University of Chemical Technology, Beijing 100029, P. R. China

ACS Paragon Plus Environment


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ABSTRACT:

19

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F magnetic resonance imaging (MRI), due to its high sensitivity and negligible

background, is anticipated to be a powerful noninvasive, sensitive and accurate molecular imaging technique. However, the major challenge of

19

F MRI is to increase the number of

19

F

atoms while maintains the solubility and molecular mobility of the probe. Here, we successfully developed a facile and general strategy to synthesize the multifunctional 19F-MRI nanoprobes by encapsulating the hydrophobic inorganic nanoparticles (NPs) into a hybrid polymer micelle consisting of hydrolysates of 1H,1H,2H,2H-perfluorodecyltriethoxysilane (PDTES) and oleylamine functionalized poly succinimide (PSIOAm). Due to their good water dispersibility, excellent molecular mobility resulted from the ultrathin coating and high 19F-atom numbers, these nanoprobes generate a separate sharp singlet of 19F nuclear magnetic resonance (NMR) signal (at − 82.8 ppm) with half peak width of ~28 Hz, which is highly applicable for

19

F-MRI.

Significantly, by varying the inorganic core from metals (Au), oxides (Fe3O4), fluorides (NaYF4:Yb3+/Er3+), phosphates (YPO4) to semiconductors (Cu7S4, Ag2S, ZnS:Mn2+) NPs, which renders the nanoprobes multifunctional properties such as photothermal ability (Au, Cu7S4), magnetism (Fe3O4), fluorescence (ZnS:Mn2+), near-infrared (NIR) fluorescence (Ag2S), and upconversion (UC) luminescence. Meanwhile, the as-prepared nanoprobes possess relatively small sizes (about 50 nm), which is beneficial for long-time circulation. The proof-of-concept in vitro

19

F

NMR

and

photothermal

ablation

of

ZnS:Mn2+@PDTES/PSIOAm

and

Cu7S4@PDTES/PSIOAm nanoprobes further suggest that these nanoprobes hold wide potentials for multifunctional applications in biomedical fields. KEYWORDS: 19F magnetic resonance imaging, multifunctional nanoprobes, hydrolyztion, perfluorodecyltriethoxysilane, poly succinimide


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INTRODUCTION Magnetic resonance imaging (MRI) is a non-invasive technique with high spatial resolution and deep penetration properties, which has been served as a prevalent diagnostic method.1-3 In recent years, 19F MRI has attracted great interest because 19F nucleus owns almost equivalent sensitivity to that of 1H, and negligible endogenous background interference, which allows quantitative analysis by direct measurement of

19

F signals of probes.4-7 However, the strong hydrophobicity

and relatively low sensitivity of fluorinated molecular probes limit their extensive applications in 19

F MRI.8 In order to obtain highly sensitive

19

F-MRI probes, small molecules with

multi-identical fluorine atoms such as perfluorocarbon (PFCs) and perfluoropolyether (PFPEs) were emulsified with liposomes, micelles and surfactants, and thus served as molecular tracers.9-11 Amphiphilic hyperbranched fluoropolymers were also synthesized and their micelles were constructed as 19F MRI agents.12-15 Alternatively, high payload of fluoric compounds on the surface of various functional inorganic nanoparticles (NPs) provides great opportunities for the construction of multifunctional nanoprobes with ultrahigh response of

19

F MRI signal, which is

highly desirable for simultaneous imaging tracking and therapeutic purposes.4, 10, 16, 17 In these cases, it is important and still challenging to increase the fluorine content in the nanoprobes and meanwhile ensure sufficient mobility of the fluorine moieties, which is essential for obtaining strong and sharp

19

F NMR peaks, and thus good

19

F MRI performance.18-20 The work of

Pasquato’s group about the fabrication of water-soluble gold NPs by coating with fluorinated amphiphilic thiolates was the first report on fluorinated inorganic NPs which potentially inspired the development of

19

F MRI probes based on inorganic nanoplatforms.21 Kikuchi’s group



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developed a multifunctional 19F MRI probe by encapsulating liquid perfluorocarbon with a robust silica shell, which has superior sensitivity and sufficient in vivo stability with an average size of ~ 80 nm.17 In another aspect, the surface functionalization of inorganic NPs is always prerequisite and crucial for biomedical applications.22, 23 Several surface functionalization strategies have been extensively utilized for fabrication of multifunctional nanocomposites such as ligand exchange, silanization, and encapsulation with amphiphilic polymers and lipids.23-26 Ligand exchange and silanization are most commonly used because they are widely applicable for transferring hydrophobic NPs into water phase. As for ligand exchange, one approach involves direct exchange of the original organic layer with hydrophilic ligands containing functional groups with stronger adherence to the surface of NPs, such as thiols and amines.27-30 Alternatively, a prevailing approach is based on the introduction of an amphiphilic ligand (polymers or lipids) to assemble onto NP surface, which forms an interdigitated bilayer with the original ligands via the hydrophobic interactions.29, 31-33 Poly-succinimide (PSI) and its derivatives have been widely investigated and considered as excellent surface modification agents, due to their biodegradability by proteolytic enzymes, and good biocompatability.34 In our previous reports, oleylamine modified (by aminolysis reaction) poly-succinimide (PSIOAm) has been successfully used to encapsulate and transfer hydrophobic nanocrystals with various shapes, sizes and chemical compositions into water phase for applications such as biosensing,31, 35 bioimaging,36 and drug delivery.37 The hydrophobic chain of oleylamine in PSIOAm facilitates self-assembly with the organic ligands on the surface of NPs, and the subsequent hydrolysis of the remaining succinimide units (lactam rings) on the PSI backbone to form abundant carboxyl groups under


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alkaline condition renders the whole nanoprobe highly dispersible in water. Meanwhile, the abundant uncoordinated carboxyl groups are available for further surface functionalization, for example, by conjugating with bioactive or chemical molecules.33, multifunctional

38

Recently, we reported a

19

F MRI nanoprobe constructed by an one-pot encapsulation method using

PSIOAm and trimethoxy(octadecyl)silane (TMOS) as co-encapsulation agents, where the perfluoro-15-crown-5-ether (PFCE, source of 19F MRI signal) was first anchored to the surface of Cu1.75S NPs through hydrophobic interactions and then trapped within a thin silica shell formed by the hydrolysis of TMOS. These fabricated nanoprobes have been evaluated and successfully applied for both in vivo 19F MR imaging and photothermal ablation of tumors.20 However, in this case, we found that PFCE is apt to leak out if only PSIOAm coating agent applied, which is mainly ascribed to the low hydrophobic interactions between PFCE and PSIOAm or original ligand on NP surface.4, 39 Therefore, the silica shell introduced by hydrolyzation of TMOS plays a crucial role in preventing the leakage of PFCE. Although the increase of silica shell thickness would efficiently prevent the PFCE from leaking, it could further restrict the mobility of 19F-molecules and finally attenuate the

19

F-MRI signal. Therefore, it is still a great challenge to increase the

number of 19F atoms on a single inorganic nanoparticle by tightly grafting the

19

F-moieties onto

the inorganic NPs, and simultaneously retain their good mobility and thus strong 19F-MRI signal. Herein, we present a general and facile strategy for the fabrication of multifunctional

19

F

MRI nanoprobes with high 19F contents and good mobility. As shown in scheme 1, inorganic NPs are first co-encapsulated into micelles with one particle per micelle by using PSIOAm and 1H,1H,2H,2H-perfluorodecyltriethoxysilane (PDTES) as co-encapsulation agents, where PDTES with a long hydrophobic fluorine chain also acts as a source of 19F MRI signal tracer at the same



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time. Then under alkaline condition, along with hydrolyzation of the remaining lactam rings in PSI (except those aminolyzed by oleylamine, i.e. 30%) and silane part in PDTES, the multifunctional

19

F MRI nanoprobes (NPs@PDTES/PSIOAm) are obtained with good water

stability and biocompatibility. Hydrophobic inorganic NPs with various sizes and chemical compositions, including metals (Au), oxides (Fe3O4), fluorides (NaYF4:Yb3+/Er3+), phosphates (LaPO4) and semiconductors (Cu7S4, Ag2S, ZnS:Mn2+) NPs, were applied to verify the feasibility and generality of this surface fabrication strategy. The as-fabricated nanoprobes showed a strong and narrow 19F NMR peak (at −82.8 ppm) with half peak width of ~28 Hz. Meanwhile, because of encapsulation with one particle per micelle, the as-prepared nanoprobes possess small sizes (average DLS diameters about 50 nm), which will be beneficial for long-time circulation after intravenous injection by escaping from both kidney filtration (< 5.5 nm) macrophages (> 200 nm) in the reticuloendothelial system.42,

43

40, 41

and removal by

In addition, the intrinsic

optical/magnetic properties of NPs are well retained. All the results indicated that we have successfully developed a general and versatile method for the preparation of multifunctional 19F MRI nanoprobes which have great potential in disease diagnosis and therapy.

Scheme 1. Schematic diagram for the encapsulation of individual NPs into a micelle coating


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formed from self-assembly and hydrolyzation of PDTES and PSIOAm under alkaline condition. NPs: nanoparticles; PDTES: 1H,1H,2H,2H-perfluorodecyltriethoxysilane; PSIOAm: oleylamine modified poly-succinimide.

EXPERIMENTAL SECTION Chemicals and reagents. General chemicals were at least analytical grade and used as received without further purification. 1H,1H,2H,2H-perfluorodecyltriethoxysilane (PDTES) was obtained from J&K Scientific Ltd. (Beijing, China). Cyclohexane, N,N-dimethyl formamide (DMF), chloroform, methanol, ethanol, propanetriol, sodium hydroxide (NaOH), Cu(NO3)23H2O, AgNO3, NaH2PO4·2H2O, Na2HPO4·12H2O, MnCl2, Na2S, ZnCl2 and HAuCl4·2H2O were supplied by Beijing Chemical Works (Beijing, China). Oleylamine was obtained from Acros (USA). Hydrofluoric acid, oleic acid, sodium stearate, 1-octadecene, and 1-dodecanethiol were purchased from Aldrich (USA). N,N-Dibutyldithiocarbamate (NNDB) was obtained from Pacific Ocean United Petro-Chemical Co., Ltd. (Beijing, China). Fe(NH4)2(SO4)2·6H2O was bought from Tianjin Fuchen Chemicals Co., Ltd. (Tianjin, China). All the rare-earth nitrates were purchased from Beijing Ouhe Chemical Reagent Co., Ltd. (Beijing, China). Poly-succinimide (PSI) (Mw ~7000) was supplied by Shijiazhuang Desai Chemical Company (Shijiazhuang, China). Ultrapure water was obtained by treating with a MilliQ water purification system from Millipore (Bedford, MA, USA).

Characterization.

19

F NMR experiments were performed on a Bruker Avance-III 400

spectrometer at 376.47 MHz by utilizing a “single pulse” sequence (Bruker “zg” sequence)



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without decoupling of 1H. Samples were dissolved in water or PBS buffer solution (pH 7.4) by using a coaxially D2O-filled capillary for locking the field. Sodium trifluoroacetate (CF3COONa) was employed as an external standard for quantification which was dissolved in water with a coaxial D2O capillary as well for locking. Transmission electron microscopy (TEM) images were collected by using a JEOL JEM-1200EX (100 KV) analytical transmission electron microscope. Dynamic light scattering (DLS) particle size analysis was carried out using a Zetasizer Nano-ZS90 zeta and size analyzer from Malvern.

Preparation of Cu7S4 nanoparticles (NPs).44 Copper nitrate (Cu(NO3)23H2O, 48.4 mg) and dibutyldithiocarbamate (NNDB, 42 mg) were dissolved in ethanol (1 mL) under continuous ultrasonication treatment (in water bath) to afford a transparent precursor solution. Oleylamine (4 mL) and 1-octadecene (6 mL) were introduced into a three-necked flask under nitrogen (N2) purging for 10 min. Under continuous stirring, the mixture solution was heated to 205 °C, then the transparent precursor solution prepared above was rapidly injected into the flask and the temperature was kept at 190 °C for another 15 min. After cooling to room temperature, the Cu7S4 NPs were collected by precipitation with ethanol and then centrifugation twice (the precipitate was redispersed in cyclohexane before the second time). The final product was dispersed in chloroform (2.0 mL) for further use.

Preparation of Ag2S NPs.45 AgNO3 (42.2 mg) and NNDB (54 mg) were dissolved in ethanol (1 mL) under continuous ultrasonication treatment (in water bath) to afford a precursor solution. Propanetriol (4 mL), 1-dodecanethiol (6 mL), and oleylamine (0.4 mL) were introduced


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into a three-necked ﬂask under the constant purging of nitrogen gas for 15 min at room temperature. Under the continuous stirring, the mixture was heated to 215 °C, and then the precursor solution prepared above was rapidly injected into the flask and the temperature was kept at 210 °C for another 15 min. After cooling to room temperature, the upper layer containing the Ag2S NPs was collected and further purified by precipitation with ethanol. The final product was stored in chloroform (2.0 mL) for later use.

Preparation of ZnS:Mn2+ NPs.45 Sodium hydroxide (0.6 g), deionized water (5 mL), ethanol (8 mL), and oleic acid (10 mL) were introduced successively into a 50-mL Teflon lined autoclave under vigorous agitation to afford a uniform buffer system. The mixture of ZnCl2 aqueous solution (1 M, 1.9 mL) and MnCl2 aqueous solution (1 M, 100 µL) was then added into the above buffer solution. Thereafter, Na2S (1 M, 2.25 mL) aqueous solution was further added and the resultant mixture was kept stirring vigorously for another 15 min to remove the generated H2S. The autoclave was then sealed and heated in an oven setting 160 °C for 8 h. After cooling to room temperature and removing the supernatant, the crude product of ZnS:Mn2+ nanoparticles was dissolved in cyclohexane and collected for further purification. The final product was obtained by washing with ethanol and centrifugation (7,000 rpm, 4 min) for twice, and then redispersed into 2 mL of chloroform for later use.

Preparation of Au NPs.45 Sodium hydroxide (0.1 g), deionized water (5 mL), ethanol (15 mL), oleic acid (2 mL), oleylamine (1 mL), and cyclohexane (5 mL) were introduced into a 50-mL Teflon lined autoclave stepwise under magnetic stirring. Then, 5 mL of chloroauric acid



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aqueous solution (2 mg/mL) and 2 µL of 1-dodecanethiol (contained in 20 µL of cyclohexane solution) were further added into the above mixture solution under vigorous stirring. The autoclave was then sealed and heated in an oven setting as 100 °C for 10 h. After cooling to room temperature, the crude product was washed with cyclohexane and ethanol and centrifuged to afford the final required Au nanoparticles, which were redispersed into 1 mL of chloroform for further experiment.

Preparation of YPO4 NPs.46 Sodium hydroxide (0.6 g), deionized water (5 mL), ethanol (10 mL), and oleic acid (10 mL) were introduced into a 50-mL Teflon lined autoclave one by one under magnetic stirring. Then NaH2PO4·2H2O aqueous solution (0.2M, 5 mL), and Y(NO3)3 aqueous solution (0.2 M, 5 mL) were added successively. Thereafter, another 10 mL of ethanol was added to fill up the autoclave. After further stirring for 10 min, the autoclave was sealed and heated in an oven setting as 140 °C for 8 h. The final product was obtained by washing with cyclohexane and ethanol and centrifugation, and then redispersed and stored in 1 mL of chloroform.

Preparation of NaYF4:Yb3+/Er3+/Gd3+ NPs.47, 48 Sodium stearate (0.35 g), oleic acid (7 mL), and octadecene (8 mL) were introduced into a three-necked flask under stirring and purging with nitrogen (N2) for 10 min to remove the air. The resulting mixture solution was heated to 80 °C, afterwards, 4 mL of the as-prepared precursor solution (the rare-earth oleate solution) and 1.4 mL of R-NH3+F- (prepared by mixing well 3 mL of HF, 17 mL of oleylamine, 3 mL of cyclohexane and 7 mL of ethanol; R is the long alkyl chain of oleylamine, C18) solution were quickly injected


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into the flask successively and the temperature was kept at 80 °C for 20 min. Then, the reaction solution was heated to 180 °C and kept for 10 min, further heated to 310 °C and kept for 30 min. And then, 0.25 g of Gd3+-oleate precursor was added into the flask and the reaction was kept for another 30 min at 310 °C under stirring. After cooling to room temperature, the crude product was collected and further purified by washing with cyclohexane (for dispersing) and ethanol (for precipitation) and then centrifugation (7000 rpm，5 min) for twice. The final product was redispersed into 4 mL of chloroform for later experiment. The rare-earth oleate precursor solution was prepared as follows: sodium hydroxide (0.384 g), deionized water (6 mL), oleic acid (3 mL), ethanol (4 mL), and cyclohexane (15 mL) were successively introduced into a 50-mL Teflon lined autoclave under stirring. The mixture aqueous solution of Y(NO3)3, Yb(NO3)3 and Er(NO3)3 (0.5 M, Y3+:Yb3+:Er3+ = 80:15:5 mol %) was then added and the resultant mixture was heated to 80 °C and kept for 4 h. After cooling to room temperature, the water layer was removed and the rare-earth oleate solution was collected.

Preparation of NaYF4 NPs.47, 48 The synthetic and purification procedure of NaYF4 NPs is similar to that of NaYF4:Yb3+/Er3+/Gd3+NPs, except that no Gd3+-oleate precursor was added and the precursor solution was prepared with slight revision as follows: sodium hydroxide (0.384 g), deionized water (6 mL), oleic acid (3 mL), ethanol (4 mL), and cyclohexane (15 mL) were successively introduced into a 50-mL Teflon lined autoclave under stirring. Y(NO3)3 aqueous solution (0.5 M, 10 mL) was then added and the resultant mixture was heated to 80 °C and kept for 4 h. After cooling to room temperature, the water layer was discarded and the rare-earth oleate solution was collected as the precursor solution.



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Preparation of Fe3O4 NPs.49 Sodium hydroxide (1.0 g), deionized water (10 mL), ethanol (10 mL), and oleic acid (10 mL) were introduced successively into a 50-mL Teflon lined autoclave

under

magnetic

stirring

to

afford

a

transparent

buffer

solution.

Then,

Fe(NH4)2(SO4)2·6H2O aqueous solution (0.2 mM, 10 mL) was added and the resultant mixture was kept stirring for 30 min. Thereafter, the autoclave was sealed and heated at 180 °C for 10 h. After cooling to room temperature, the crude product of Fe3O4 nanoparticles was collected and further purified by washing with chloroform (for dispersing) and ethanol (for precipitation) and centrifugation (6000 rpm, 4 min) for twice. The obtained final product was then stored and redispersed in 1 mL of chloroform.

Preparation of PSIOAm.36 Under constant stirring, poly-succinimide (PSI, 1.6 g) was dissolved in DMF (32 mL) at 90 °C, and oleylamine (2.16 mL) was added afterwards. The resulting mixture solution was kept stirring at 100 °C for 5 h to afford a clear and transparent solution. Thereafter, the final product was collected by precipitation with methanol and then centrifugation (7000 rpm, 4 min). Finally, the object product (PSIOAm) was redispersed in chloroform (8.0 mL) for further experiment.

Fabrication of multifunctional individual NPs. The as-prepared hydrophobic NPs, including Cu7S4, Ag2S, ZnS:Mn2+, Au, YPO4, NaYF4, NaYF4:Yb3+/Er3+/Gd3+, and Fe3O4 were functionalized by co-encapsulation with PSIOAm and PDTES and thus transferred into water medium. The modification and functionalization procedure for all the NPs was same except for


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the amount of the NPs used. Taking the modification of ZnS:Mn2+ NPs as an example. The as-prepared ZnS:Mn2+NPs (7 mg), PSIOAm (10 mg) and PDTES (28 mg) were dissolved in 1.0 mL of chloroform. The mixture was then added into 10 mL of NaOH aqueous solution (20 mM). After the resultant mixture solution changed into emulsion under ultrasonication treatment (380 W，6 min，pulsed working as 3 s “on” and 3 s “off”), it was further stirred at ambient temperature (~28°C) for 5 h to remove the chloroform, and simultaneously keep the hydrolyzation of PDTES and thus being anchored to the surface of NPs. The resultant solution was further centrifuged and washed twice with water, and the final product (ZnS:Mn2+@PDTES/PSIOAm) was collected and then transferred into1 mL of deionized water.

Cell

viability

assessment.

The

cytotoxicity

of

the

fabricated

hydrophilic

ZnS:Mn2+@PDTES/PSIOAm and Cu7S4@PDTES/PSIOAm nanoprobes was evaluated via the methyl thiazolyltetrazolium(MTT) method against HeLa cell lines. About 5×104 cells/well were seeded in a 96-well microtiter plate, then different amounts of the nanomaterials (from 0 to 400 µg/mL) were added and cultured at 37 °C under 5% CO2 and a 95% relative humidity atmosphere. Cytotoxicity was assessed at 24 h and 48 h post-treatment, respectively. After 10 µL of sterile-ﬁltered MTT stock solution in PBS (4.0 mg/mL) was added into each well of the microtiter plate, it was then incubated at 37 °C for another 3 h. Only the viable cells can induce the cellular reduction of MTT, which will produce the soluble colored formazan. Then the absorbance of the produced formazan in each well can be measured at 490 nm on an ELISA plate reader (F50, TECAN). The cell viability can be calculated from the absorbance compared to that of the control group.



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RESULTS AND DISCUSSION

Fabrication and Characterization of Nanoprobes. To verify the feasibility and generality of this facile functionalization method, different inorganic nanomaterials with different sizes and chemical compositions were functionalized and transferred into aqueous medium. As shown in Figure 1, all the hydrophobic NPs including photothermal semiconductors (Cu7S4, 12.6±1.4 nm), fluorescent quantum dots (ZnS:Mn2+, 4.2±1.0 nm), near-infrared (NIR) fluorescence quantum dots (Ag2S, 6.3±1.4 nm), noble metals (Au, 9.8±3.2 nm), upconversion (UC) luminescent fluorides (NaYF4:Yb3+/Er3+/Gd3+, 17.4±1.0 nm; NaYF4, 15.8±2.0 nm), phosphates (YPO4, 44.4 ± 10.9 nm), and magnetic oxides (Fe3O4, 5.4 ± 1.2 nm) have been successfully encapsulated into the PDTES/PSIOAm micelle with one particle per micelle. Transmission electron microscopy (TEM) images of these NPs before (Figure 1, a1~c1; Figure 2, a1~c1; Figure 3, a1~b1) and after (Figure 1, a2~c2; Figure 2, a2~c2; Figure 3, a2~b2) surface modification indicated negligible changes in particle shape and size, and no aggregation of particles was observed. Moreover, NPs@PDTES/PSIOAm kept well dispersed and stable in water (Figure 1, a3~c3; Figure 2, a3~c3; Figure 3, a3~b3), due to the assembly of micelle during the hydrolyzation of PDTES and PSIOAm which formed an oil-in-water type layer around the surface of NPs. In addition, the most important advantage for the as-prepared hydrophilic NPs@PDTES/PSIOAm nanoprobes is that they demonstrate strong and sharp 19F nuclear magnetic resonance (NMR) signal (Figure 1, a4~c4; Figure 2, a4~c4), which endows the nanoprobes great potential for

19

F magnetic resonance

imaging (MRI) application. Typically, the singlet fluorine resonance at −82.8 ppm (assigned to the trifluoromethyl of PDTES) is separate and sharp with a half width of ~28 Hz which is narrow


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enough for MRI applications.50 Along with the evaporation of chloroform from the micelle, the 19

F chain of PDTES remains desired mobility in the gap between the polymer coating and NPs

surface,

thus

acquires

expected

sharp

19

F

NMR

peaks.

As

for

NaYF4:Yb3+/Er3+/Gd3+@PDTES/PSIOAm and Fe3O4@PDTES/PSIOAm, weak (Figure 3, a4) or vanished (Figure 3, b4) 19F NMR signals were observed, which were ascribed to the paramagnetic relaxation enhancement (PRE) effect from paramagnetic metal ions such as Gd3+ and Fe3+ adjacent to the 19F moieties.51

Figure 1. TEM images (a1-c1 & a2-c2) and optical photographs (a3-c3) of various NPs (Cu7S4, Ag2S, ZnS:Mn2+) before (a1-c1) and after (a2-c2) surface modification with PDTES/PSIOAm and the corresponding 19F NMR spectra (a4-c4). The amount of PDTES applied here was 20 µL, and the solvents (upper and lower part) in the vials (a3-c3) were water and chloroform, respectively.



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Figure 2. TEM images (a1-c1 & a2-c2) and optical photographs (a3-c3) of various NPs (Au, YPO4, NaYF4) before (a1-c1) and after (a2-c2) surface modification with PDTES/PSIOAm and the corresponding 19F NMR spectra (a4-c4). The amount of PDTES applied here was 20 µL, and the solvents (upper and lower part) in the vials (a3-c3) were water and chloroform, respectively.

Figure 3. TEM images (a1-b1 & a2-b2) and optical photographs (a3-b3) of various NPs (NaYF4:Yb3+/Er3+/Gd3+, Fe3O4) before (a1-b1) and after (a2-b2) surface modification with


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PDTES/PSIOAm and the corresponding

19

F NMR spectra (a4-b4). The amount of PDTES applied

here was 20 µL, and the solvents (upper and lower part) in the vials (a3-b3) were water and chloroform, respectively.

Biomedical Evaluation. For the fabrication of multifunctional

19

F MRI probes based on

inorganic NPs, on the other hand, it is of great importance to maintain the intrinsic properties of NPs after modification. As representatives, Cu7S4 and ZnS:Mn2+ NPs were further selected to testify the generality of this fabrication strategy for biomedical applications. The most attractive feature of this fabrication method is that PDTES serves as both 19F functional moiety donors and co-capping agents, thus affords inorganic NPs

19

F-MRI functionality and water dispersibility

simultaneously. Therefore, we first investigated the impact of different amounts of PDTES on the morphology, size distribution, and

19

F NMR signals of the nanoprobes. As shown in the TEM

images (Figure 4a1-f1), the NPs demonstrated very good dispersibility with the increase of PDTES, while the dynamic light scattering (DLS) size (Figure 4a2-f2) of Cu7S4@PDTES/PSIOAm was slightly increased due to a thin layer of silica coating formed via hydrolysis of PDTES. Unlike tetraethoxysilane (TEOS) which is frequently used as a silica coating agent and can grow around NPs layer by layer via hydrolysis, PDTES has a strong hydrophobic chain that could hamper the continuous layer by layer hydrolyzation on the surface of NPs in water medium. Thus, at high dosage of PDTES (> 20 µL), the excess PDTES would

self-assemble in the vicinity of

the NPs, which led to obvious background contamination observed in TEM images (Figure 4, e1& f1). The coating thickness on the NPs has no obvious difference, which is highly favorable for the good mobility of

19

F moieties. In another aspect, the

19

F NMR signals are linearly

correlated with PDTES dosage, yet such enhancement would reach its maximum when the



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dosage is over 25 µL (Figure 5a). Moreover, the half peak width of fluorine peak (−82.8 ppm) remains almost unchanged (~29 Hz) with PDTES dosage in the range from 5 to 20 µL, and slightly increases to ~33 Hz at higher dosage of 30 µL (Figure 5b), which is highly desirable for 19

F MRI. In addition, Figure S1 (Supporting Information) and Figure S2 (Supporting Information)

also demonstrated the similar results for ZnS:Mn2+@PDTES/PSIOAm nanoprobes to those aforementioned for Cu7S4@PDTES/PSIOAm, suggesting that this fabrication method is a general strategy for multifunctional 19F-MRI nanoprobes.

Figure 4. TEM images (a1-f1) and DLS size distribution (a2-f2) of the Cu7S4@PDTES/PSIOAm nanoprobes prepared with different volumes of PDTES: (a1, a2) 5 µL, (b1, b2) 10 µL, (c1, c2) 15 µL, (d1, d2) 20 µL, (e1, e2) 25 µL, and (f1, f2) 30 µL.


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Figure 5. (a) Plot of fluorine concentration in Cu7S4@PDTES/PSIOAm colloids versus the volume of PDTES added during the preparation of PDTES/PSIOAm nanoprobes. The fluorine concentration was calculated by external standard method using CF3COONa as a standard compound for

19

F quantitation; (b) The

19

F NMR peak at −82.8 ppm with different amounts of

PDTES used for the preparation of Cu7S4@PDTES/PSIOAm nanoprobes. The fluorine peak at −82.8 ppm is assigned to the trifluoromethyl of PDTES.

In

addition,

the

effects

of

temperature

and

pH

on

19

F

MR

signals

of

ZnS:Mn2+@PDTES/PSIOAm and Cu7S4@PDTES/PSIOAm were further investigated (Figure 6). NMR tubes filled with the colloidal solution of the probes were put into water bath set at different temperatures (from room temperature to 90 °C), after incubation for 30 min,


19

F NMR spectra


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were acquired. With the increase of temperature,

19

Page 20 of 35

F MR signals maintained negligible change

even at 90 °C (Figure 6a, b). As for the pH effect (Figure 6c, d), around pH value from 7 to 8, signal-to-noise ratio (SNR) of 19F signals kept relatively stable. However if the pH was too low (pH 5) or too high (pH 9), the signal intensity showed a slight decrease.

Figure 6. Effect of temperature (a, b) and pH (c, d) on

19

F MR signals of

ZnS:Mn2+@PDTES/PSIOAm (a, c) and Cu7S4@PDTES/PSIOAm (b, d), respectively. All the tests were repeated three times.

Cytotoxicity Assessment. In order to investigate the potential bioapplications of the as-fabricated


and

Cu7S4@PDTES/PSIOAm nanoprobes,

their

cytotoxicity evaluation was then carried out on HeLa cells via the MTT assay. As shown in Figure

7,

when

incubated

with

120

µg/mL

of


or

Cu7S4@PDTES/PSIOAm colloidal solution for 24 h, over 88% and 95% cells were alive,


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respectively. Even at the high concentration of ZnS:Mn2+@PDTES/PSIOAm (400 µg/mL) and Cu7S4@PDTES/PSIOAm (200 µg/mL), the viability of cells was still over 80% after incubation for 48 h, suggesting very satisfied biocompatibility of the NPs after surface functionalization.

Figure 7. Cytotoxicity tests of ZnS:Mn2+@PDTES/PSIOAm (a) and Cu7S4@PDTES/PSIOAm (b) colloids after incubation with HeLa cell lines for 24 h and 48 h, respectively. For each concentration, eight parallel tests were performed.

Cellular

Uptake

Investigation.

Next,

the

probability

of

19

F

MRI

of

ZnS:Mn2+@PDTES/PSIOAm nanoprobes within Hela cells was further evaluated. The time and dose dependent cellular uptake of ZnS:Mn2+@PDTES/PSIOAm nanoprobes was analyzed by

19

F

NMR spectroscopy. Hela cells were co-incubated with different concentrations (1.6-8.0 mg/mL) of ZnS:Mn2+@PDTES/PSIOAm for 8 h, and incubated for various time intervals at the fixed concentration of 8.0 mg/mL, respectively. After washing with buffer, the cells were lysed and the lysates were analyzed. As expected, the

19

F NMR spectroscopy showed obvious cellular uptake

of ZnS:Mn2+@PDTES/PSIOAm as a sharp (half peak width is around 28 Hz) singlet peak at −82.8



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ppm. At the fixed concentration (8.0 mg/mL) of ZnS:Mn2+@PDTES/PSIOAm,

Page 22 of 35

19

F MR signal

intensities increased along with the increase of incubation time and reached a maximum till 8 h (Figure 8a). Alternatively, with same incubation time of 8 h, a linear relationship between the incubation dosage and cellular uptake of ZnS:Mn2+@PDTES/PSIOAm was observed (Figure 8b). Moreover, the half peak width of 19F MR signals in cell lysate matrix kept almost unchanged as compared to that in PBS solution, which indicated that no obvious aggregation of the probes happened in biological interference environment. These observations demonstrated the potential utility of ZnS:Mn2+@PDTES/PSIOAm as a bimodal imaging probe for simultaneous

19

F MR and

fluorescence imaging.

Figure 8. 19F NMR signal intensities (peak at −82.8 ppm) of the cell lysates after incubation with different time intervals at 8.0 mg/mL of ZnS:Mn2+@PDTES/PSIOAm nanoprobes (a), and various concentrations of the probes for 8 h (b), which indicated time and dose dependent uptake of


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ZnS:Mn2+@PDTES/PSIOAm by HeLa cells, respectively. The numbers above the spectra are half peak width (in Hz) of 19F MR signals.

Photothermal Evaluation of Cu7S4@PDTES/PSIOAm. It is known that Cu7S4 NPs possess strong and broadband absorption and show superior near infrared (NIR) photothermal efficacy due to the localized surface plasmon resonance (LSPR) effect.44, 52 Therefore, the photothermal effect of the as-prepared Cu7S4@PDTES/PSIOAm nanoprobes was further examined (Figure 9). It was found that the higher of the concentration, the brighter of the induced photothermal images under fixed power densities. Alternatively, if same amount of nanoparticles were used, the higher of the power densities would result in stronger photothermal effect (Figure 9a). Additionally, the temperature evolution profile (Figure 9b) showed that the temperature of the nanoprobe solution increased rapidly from 30 to 55 °C within 3 min at 16 mg/mL of Cu7S4@PDTES/PSIOAm and 1.5 W/cm2 of NIR light irradiation, indicating the excellent photothermal conversion efficacy of the as-fabricated Cu7S4@PDTES/PSIOAm nanoprobes. Combined with the favorable 19F MR imaging property, these nanoprobes could be potentially used as a multifunctional medical agent for MRI imaging guided photothermal therapy.



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Figure 9. (a) Photothermal images of the Cu7S4@PDTES/PSIOAm colloidal solution with different concentrations (4-32 mg/mL) and under different power densities (0.25-1.5 W/cm2) of NIR light irradiation (808 nm) for 180 s; (b) Temperature evolution profile of Cu7S4@PDTES/PSIOAm in water medium at 16 mg/mL of nanoprobes and 1.5 W/cm2 of NIR light irradiation.

To investigate the photothermal therapy potential of the Cu7S4@PDTES/PSIOAm nanoprobes, photothermal ablation effect on HeLa cells was further performed (Figure 10). After incubation with different amounts of Cu7S4@PDTES/PSIOAm nanoprobes for 8 h, light irradiation (3 min) resulted in obvious lower viability of the HeLa cells compared to that in the absence of light. On the other hand, although without light irradiation, cell viability also decreased gradually due to


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the cytotoxicity at higher concentration of probes. However, the cytotoxicity was negligible when the concentration was under 2 mg/mL (Figure 10a). Afterwards, HeLa cells were incubated with 2 mg/mL of Cu7S4@PDTES/PSIOAm for 8 h, then exposed to NIR light (808 nm, 1.0 W/cm2) for various time from 0 to 3 min. As shown in Figure 10b, the light irradiation induced obvious cell death after exposure to 808-nm light (1.0 W/cm2) for 1 min. It is noteworthy that the relatively weak photothermal therapy efficiency could be attributed to the heat dissipation of cell culture media because the cells were still incubated in culture media during the photothermal treatment.

Figure 10. Photothermal ablation effect of Cu7S4@PDTES/PSIOAm nanoprobes on HeLa cells after co-incubation for 8 h. Cell viability versus various concentrations under NIR light irradiation (808 nm) for 3 min (a) and versus different time intervals of light irradiation (808 nm) at fixed concentration (2.0 mg/mL) (b). The power density of the light irradiation is 1.0 W/cm2. All the tests were repeated three times.

CONCLUSION In summary, we have demonstrated a facile and general strategy for the fabrication of


19

F-MRI


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Page 26 of 35

multifunctional nanoprobes with strong 19F signals and good water-dispersibility as well as good biocompatibility. By co-encapsulating with PSIOAm and PDTES under alkaline condition, inorganic NPs with different sizes, shapes, and chemical compositions were successfully fabricated into multifunctional nanoprobes. In addition, this method has no obvious impacts on the structures and intrinsic (optical/magnetic) properties of the core NPs. The cellular uptake and 19

F NMR investigations, together with the photothermal effect assessment of the representative

nanoprobes (ZnS:Mn2+ and Cu7S4 as core NPs) demonstrated great potential for biomedical applications. Although we cannot carry out the in vivo applications right now, this work still provides a general way to fabricate the multifunctional nanoprobes with strong

19

F MRI signals

and good biocompatibility, which will ignite the interests in the corresponding research communities such as chemistry, nanomaterials, and medicinal technology.

ASSOCIATED CONTENT

Supporting Information. TEM images, the size distribution (Figure S1), and

19

F NMR spectra

(Figure S2) of ZnS:Mn2+@PDTES/PSIOAm nanoprobes prepared with different amounts of PDTES, as well as the plot of fluorine concentration in ZnS:Mn2+@PDTES/PSIOAm versus the volume of PDTES used (Figure S2).

AUTHOR INFORMATION Corresponding Author


Page 27 of 35

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*E-mail: [email protected]. Phone: +86-10-64433197.

Author Contributions The manuscript was written through contributions of all authors. All authors have given approval to the final version of the manuscript.

Notes The authors declare no competing financial interest.

Acknowledgements This research was supported in part by the National Natural Science Foundation of China (21475007 and 21275015) and the Fundamental Research Funds for the Central Universities (YS1406, buctrc201507and buctrc201608). We also thank the support from the “Innovation and Promotion Project of BUCT”, the “Public Hatching Platform for Recruited Talents of BUCT” and BUCT Fund for Disciplines Construction and Development (Project No. XK1526).

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A General and Facile Strategy to Fabricate Multifunctional

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